The prognosis of patients with relapsed or refractory acute lymphocytic leukemia (ALL) is extremely poor and it has not changed over the last decade. Our group has extensively studied the role of aberrant DNA methylation in patients with ALL. We have demonstrated that aberrant DNA methylation of multiple promoter associated CpG islands is a very frequent phenomenon in ALL, and that aberrant epigenetic silencing of specific molecular pathways, in particular a cell cycle control pathway, predicts for very poor prognosis in patients with ALL. These methylation alterations are stable at the time of relapse and can be detected at the time of initial remission in patients at high-risk for relapse. Data from our laboratory also indicates that the in vitro sensitivity of lymphoid cells to the hypomethylating agent 5-aza-2'-deoxycytidine is similar to that observed in myeloid leukemic cells. Furthermore, data from several phase I studies conducted at our institution of low dose 5-aza-2'-deoxycytidine have indicated that a low dose schedule is safe and active in patients with advanced acute leukemias. Based on this information, we propose the hypothesis that a low dose schedule of 5-aza-2'-deoxycytidine will be safe and active in patients with relapsed/refractory ALL used either as a single agent or in combination with hyperCVAD chemotherapy, and that this therapy is associated with changes in global and gene specific methylation and gene expression patterns. To test this hypothesis, we propose the following Specific Aims: #1) To conduct a phase I study of low dose 5-aza-2'-deoxycytidine in patients with relapsed/refractory ALL. Based on prior data, we have designed a schedule that consists in the administration of 5-aza-2'- deoxycitidine daily for 5 days every other week. If patients do not respond or progress to 5-aza-2'-deoxycytidine, a subsequent phase of the study will consist in the combination of 5-aza-2'-deoxycytidine with hyperCVAD based chemotherapy. #2) To analyze changes in global and gene specific aberrant DNA methylation and gene expression patterns sequentially during the above therapy. The implications of this study are multiple and of importance. This include: 1) the potential development of a new therapeutic alternative for patients with advanced ALL; 2) the analysis of the dynamics of methylation/expression changes during epigenetic therapy in ALL; and 3) crucial information for the incorporation of 5-aza-2'-deoxycytidine up-front therapy for patients with untreated ALL. There is no active treatment for relapsed or refractory acute lymphocytic leukemia, the most common cancer in children. In this proposal, we plan to develop a new form of low-dose chemotherapy, decitabine, for these patients. Early results indicate that this is active and safe. [unreadable] [unreadable] [unreadable]